EP0643058B1 - Cristaux d'un composé antimicrobien - Google Patents
Cristaux d'un composé antimicrobien Download PDFInfo
- Publication number
- EP0643058B1 EP0643058B1 EP94114235A EP94114235A EP0643058B1 EP 0643058 B1 EP0643058 B1 EP 0643058B1 EP 94114235 A EP94114235 A EP 94114235A EP 94114235 A EP94114235 A EP 94114235A EP 0643058 B1 EP0643058 B1 EP 0643058B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- weak
- hydrate
- fluorocyclopropyl
- azaspiro
- dihydroquinoline
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
Definitions
- This invention relates to crystals of compound (I) without water of crystallization (hereinafter referred to as anhydrate form or anhydrate, simply), to a method for selectively preparing these crystals and crystals containing water of crystallization (hereinafter referred to as hydrate form or hydrate, simply), and further to pharmaceutical preparations containing such a crystalline form.
- the compound (I) can exist in the form of several kinds of hydrate forms other than a 1/4 (0.25) hydrate, such as a 1/2 (0.5) hydrate (i.e., hemihydrate), a 1 hydrate (i.e., monohydrate), and a 3/2 (1.5) hydrate (i.e., sesquihydrate, see JP 90/279 778). It was also found that an anhydrate form exists in addition to these hydrates.
- Hydrate form of compound (I) include plural types of crystals having different number of crystal water molecules. Depending on the conditions for crystallization or recrystallization, plural types of hydrates are formed in the resulting crystals, and such crystals are unsuitable as a bulk material for solid pharmaceutical preparations.
- the present invention relates to a method for selectively obtaining a 3/2 hydrate of compound (I) in crystalline form which comprises treating 7-[(7-(S)-amino-5-azaspiro[2.4]heptan-5-yl]-8-chloro-6-fluoro-1-[(1R,25)-2-fluorocyclopropyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid in an aqueous solvent wherein the minimum water content of said aqueous solvent depends on the temperature such that said water content is at least 40 % at 25°C and at least 90 % at 60°C, or recrystallizing 7-[(7-(S)-amino-5-azaspiro[2.4]heptan-5-yl]-8-chloro-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
- the present invention relates to a method for selectively obtaining a 3/2 hydrate of compound (I) in crystalline form which comprises treating 7-[(7-(S)-amino-5-azaspiro[2.4]heptan-5-yl]-8-chloro-6-fluoro-l-[(1R,2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid in an aqueous solvent, wherein the minimum water content of said aqueous solvent depends on the temperature such that said water content is at least 40 % at 25°C and at least 90 % at 60°C.
- the present invention relates to a method for selectively obtaining a 3/2 hydrate of compound (I) in crystalline form which comprises recrystallizing 7-[(7-(S)-amino-5-azaspiro[2.4]heptan-5-yl]-8-chloro-6-fluoro-l-[(1R,2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid from an aqueous solvent, wherein the water content of said aqueous solvent is in the range of 50 % to 100 %, preferably 50 % to 75 %.
- the present invention also relates to the aforementioned methods, wherein the aqueous solvent is an aqueous ethanol containing ammonia.
- the present invention also relates to a method for selectively obtaining 7-[(7-(S)-amino-5-azaspiro[2.4]heptan-5-yl]-8-chloro-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 3/2 hydrate in crystalline form which substantially has the following X-ray diffraction characteristics: d Value (lattice spacings) ( ⁇ ) Relative Intensity 11.47 Weak 10.49 Strong 9.69 Weak 7.12 Extremely Weak 6.87 Strong 6.23 Strong 5.68 Weak 5.25 Strong 4.90 Extremely Strong 4.71 Extremely Weak 4.61 Weak 4.25 Weak 4.15 Extremely Weak 4.01 Strong 3.85 Extremely Weak 3.80 Extremely Weak 3.74 Extremely Weak 3.69 Weak 3.58 Weak 3.50 Weak 3.46 Weak 3.39 Weak 3.34 Weak 3.29 Weak 3.17
- the present invention also relates to 7-[(7-(S)-amino-5-azaspiro[2.4]heptan-5-yl]-8-chloro-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid anhydrate.
- the present invention further relates to pharmaceutical preparations containing the anhydrate mentioned above.
- the present invention also relates to an antibacterial agent comprising as an active ingredient a therapeutically effective amount of 7-[7-(S)-amino-5-azaspiro[2.4]heptan-5-yl]-8-chloro-6-fluoro-1-[(1R,25)-2-fluorocyclopropyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid an hydrate.
- the present invention also relates to the use of 7-[(7-(S)-amino-5-azaspiro[2.4]heptan-5-yl]-8-chloro-6-fluoro-1-[(1R, 2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid anhydrate for preparing a pharmaceutical composition for treating bacterial infections.
- Fig. 1 represents an example of X-ray diffraction spectrum of a 3/2 hydrate of the compound (I).
- Fig. 2 represents an example of X-ray diffraction spectrum of a 1/2 hydrate of the compound (I).
- Fig. 3 represents an example of X-ray diffraction spectrum of an anhydrate of the compound (I).
- Fig. 4 represents an example of X-ray diffraction spectrum of a 1 hydrate of the compound (I).
- the inventors studied crystals of compound (I) and, as a result, found that there are crystals of anhydrate form and hydrate forms and that the hydrate forms include a 1/2 hydrate, a 1 hydrate and a 3/2 hydrate in addition to 1/4 hydrate.
- the 3/2 hydrate is preferred because of its physicochemical stability as well as yield and ease in setting of production condition when a bulk material for pharmaceuticals is produced.
- the anhydrate is good in dissolution rate itself and from a tablet.
- each of hydrates and anhydrate of compound (I) according to the present invention exhibits the spectrum pattern shown in the drawings and has the substantially characteristic pattern of the powder X-ray diffraction spectrum shown in the following Examples.
- the term "substantially characteristic” means that the spectrum pattern of each of the crystals is not limited to that of attached figures and tables but includes errors in lattice spacings (d values) and intensity generally accepted in this field.
- the inventors examined the stability of crystals of compound (I) in an aqueous solvent or water as follows.
- an aqueous ethanol having a water content (hereinafter defined) between 0% to 100% was employed. It was also found that an aqueous ethanol further containing 1% of 28% aqueous ammonia increases solubility of the crystals and accelerates the conversion rate between hydrates.
- the solvent was used in an amount of 15 ml to 30 ml per 1 gram of the crystals.
- the water content of the solvent used is expressed in terms of volume ratio before mixing.
- an aqueous ethanol having a water content of 60% means a mixture of ethanol and water at a volume ratio of 4:6, and an aqueous ethanol having a water content of 60% containing 1% aqueous ammonia is a mixture consisting of ethanol, water and 28% aqueous ammonia at a volume ratio of 40:59:1.
- the stirring was continued for 3 days at a temperature of 25°C or 45°C.
- the time period of 3 days is not essential for conversion of crystals, and it was proved that the conversion completes in about 1 day.
- treating means continuously stirring a mixture of crystals and a solvent in a slurried state at the aforementioned temperature for the aforementioned period.
- a slurry of crystals may be prepared either by once dissolving the crystals followed by crystallization or by simply mixing the crystals and the solvent.
- the solvent which can be used in the present invention is not particularly limited as long as the crystals can dissolve in the solvent and the solvent is miscible with water.
- Illustrative examples of the solvent include lower alcohols, such as methanol, ethanol, and propanol, and acetone, of which ethanol is preferred.
- water may be used solely as a solvent.
- crystals consisting of only a 3/2 hydrate can be prepared selectively by the recrystallization which employs as conditions at the start of crystallization the above-described conditions which allow only a 3/2 hydrate to exist in a slurried state.
- the term "at the start of crystallization” as used herein means the point at which all the pretreatments before formation of crystals, e.g., dissolving crude crystals in a solvent and, if desired, subjecting the solution to a treatment with activated carbon, concentration or the like, have finished.
- the inventors also succeeded in establishing a method for obtaining a 1/2 hydrate, an anhydrate or a 1 hydrate as a single crystals by recrystallization or the treatment in a solvent by a similar manner.
- a 1 hydrate of compound (I) can be prepared by the treatment at about 25°C in an aqueous methanol having a water content of 1% or less and an anhydrate can be prepared by the treatment in an ethanol containing 15% (w/w) ammonia.
- a mixture of the crude crystal of compound (I), which can be prepared according to the method disclosed in EP-A-0 341 493, and an aqueous methanol or an aqueous ethanol is heated under reflux with stirring in a state of slurry for from 0.5 hour to 8 hours.
- the water content of the aqueous methanol or ethanol is less than 5% (v/v).
- the amount of the solvent is in the ratio of from 10 ml to 30 ml to 1 g of the crude compound (I). Increasing the water content of the solvent tends to lessen the time for completion of the treatment.
- anhydrous ethanol was employed as the solvent, the conversion completed at the temperature of 70°C and the time of 8 hours.
- the anhydrate can be obtained by the recrystallization method.
- One of the best procedure is exemplified as Example 3 explained later.
- an aqueous solvent containing less than 5% (v/v) of water can be employed as the solvent.
- a mixture of the crude crystal of compound (I) and an aqueous ethanol having a water content of 50% is heated under reflux with stirring in a state of slurry for from 1 hour to 20 hours.
- the amount of the solvent is in the ratio of from 10 ml to 30 ml to 1 g of the crude compound (I). It was known that when the solvent containing ammonia was used the rate of the formation of 1/2 hydrate was accelerated.
- the 1/2 hydrate can be obtained by the recrystallization method.
- One of the best procedure is exemplified as Example 2 explained later.
- Example 4 One of the best procedure for the selective preparation of 1 hydrate is exemplified as Example 4 explained later.
- the 3/2 hydrate is obtained from a slurry mixture stirred under the condition previously explained under which the 3/2 hydrate predominantly forms.
- the condition in which the 3/2 hydrate predominantly forms is mainly determined by the water content of the solvent and the temperature, and the relation is summarized in the following table.
- the predominant region in the slurry of 3/2 hydrate Temperature (°C) Water Content 45 more than 50% 50 more than 60% 55 more than 70% 60 more than 90%
- the amount of the solvent is in the ratio of from 10 ml to 30 ml to 1 g of the crude compound (I).
- the 3/2 hydrate can be obtained by the recrystallization procedure.
- the preferable procedure is exemplified as Examples 1 and 5 explained later.
- a solvent containing ammonia because the amount of the solvent required can be decreased.
- the amount of the solvent is in the ratio of from 5 ml to 50 ml to 1 g of the crude compound (I), and preferably from 10 ml to 20 ml.
- the water content of the solvent is in the range of from 50% to 100%, and preferably from 50% to 75%. If the content of ammonia is raised, the solvent used can be decreased.
- the amount of ammonia is in the ratio of from 0.5 g to 2.0 g, preferably from 0.7 g to 1.0 g, to 1 g of the crude compound (I).
- the solvent containing ammonia can be prepared by adding ammonia water or by introducing gaseous ammonia to the solvent. When ammonia water is employed, the water ingredient thereof needs to be calculated to obtain the solvent of precise water content.
- the temperature for crystallization can be determined according to the table above.
- the crystal of the present invention can be formulated into antimicrobial preparations in an appropriate solid preparation form by the conventional preparation methods.
- the solid preparation form for oral administration includes tablets, powders, granules and capsules.
- the active ingredient may be mixed with appropriately selected pharmaceutically acceptable excipients, such as fillers, extenders, binders, disintegrators, dissolution accelerators, wetting agents, and lubricants.
- pharmaceutically acceptable excipients such as fillers, extenders, binders, disintegrators, dissolution accelerators, wetting agents, and lubricants.
- the crystal of the invention can be formulated into preparations for animals, such as powders, fine granules, and solubilized powders by commonly employed preparation methods.
- Powder X-Ray Diffractometry characteristic peaks
- Powder X-Ray Diffractometry characteristic peaks
- d Value lace spacings
- ⁇ Relative Intensity 11.47 Weak 10.49 Strong 9.69 Weak 7.12 Extremely Weak 6.87 Strong 6.23 Strong 5.68 Weak 5.25 Strong 4.90 Extremely Strong 4.71 Extremely Weak 4.61 Weak 4.25 Weak 4.15 Extremely Weak 4.01 Strong 3.85 Extremely Weak 3.80 Extremely Weak 3.74 Extremely Weak 3.69 Weak 3.58 Weak 3.50 Weak 3.46 Weak 3.39 Weak 3.34 Weak 3.29 Weak 3.17 Weak IR; ⁇ max (KBr) cm -1 : 3450, 3000, 2880, 1620 Elemental Analysis, for C 19 H 18 F 2 ClN 3 O 3 •3/2H 2 O: Calcd. (%) C 52.24; H 4.85; N 9.62 Found (%) C 52.07; H 4.68; N 9.47 Water Content (K
- Powder X-Ray Diffractometry (characteristic peaks): Powder X-Ray Diffractometry (characteristic peaks): d Value (lattice spacings) ( ⁇ ) Relative Intensity 13.22 Strong 7.74 Extremely Strong 6.94 Extremely Weak 6.68 Weak 5.77 Weak 5.60 Strong 5.16 Extremely Weak 4.71 Medium 4.09 Strong 3.91 Weak 3.72 Weak 3.60 Strong IR; ⁇ max (KBr) cm -1 : 3620, 3410, 3080, 2870, 1630, 1610, 1540 Elemental Analysis, for C 19 H 18 F 2 ClN 3 O 3 H 2 O: Calcd. (%) C 53.34; H 4.71; N 9.82 Found (%) C 53.31; H 4.55; N 9.93 Water Content (Karl Fischer's method): Calcd.: 4.2%; Found: 4.1%
- Powder for Admixture with Feedstuff Compound of Example 1 (3/2 hydrate) 1 to 10 g Corn starch 89.5 to 98.5 g Light anhydrous silicic acid 0.5 g Total: 100 g
Claims (8)
- Procédé d'obtention sélective d'un 3/2 hydrate de l'acide 7-[(7(S)-amino-5-azaspiro[2.4]heptane-5-yl]-8-chloro-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydroquinoléine-3-carboxylique sous forme cristalline, qui comprend le traitement de l'acide 7-[(7-(S)-amino-5-azaspiro[2.4]heptane-5-yl]-8-chloro-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydroquinoléine-3-carboxylique dans un solvant aqueux, la teneur en eau minimale dudit solvant aqueux dépendant de la température de manière que ladite teneur en eau soit d'au moins 40 % à 25°C et d'au moins 90 % à 60°C, ou la recristallisation de l'acide 7-[(7-(S)amino-5-azaspiro[2.4]heptane-5-yl]-8-chloro-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydroquinoléine-3-carboxylique dans un solvant aqueux, la teneur en eau dudit solvant aqueux étant comprise entre 50 % et 100 %, de préférence entre 50 % et 75 %.
- Procédé selon la revendication 1 pour l'obtention sélective d'un 3/2 hydrate de l'acide 7-[(7-(S)-amino-5-azaspiro[2.4]heptane-5-yl]-8-chloro-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydroquinoléine-3-carboxylique sous forme cristalline, qui comprend le traitement de l'acide 7-[(7-(S)-amino-5-azaspiro[2.4]heptane-5-yl]-8-chloro-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydroquinoléine-3-carboxylique dans un solvant aqueux, la teneur en eau minimale dudit solvant aqueux dépendant de la température de manière que ladite teneur en eau soit d'au moins 40 % à 25°C et d'au moins 90 % à 60°C.
- Procédé selon la revendication 1 pour l'obtention sélective d'un 3/2 hydrate de l'acide 7-[(7-(S)-amino-5-azaspiro[2.4]heptane-5-yl]-8-chloro-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydroquinoléine-3-carboxylique sous forme cristalline, qui comprend la recristallisation de l'acide 7-[(7-(S)-amino-5-azaspiro[2.4]heptane-5-yl]-8-chloro-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydroquinoléine-3-carboxylique dans un solvant aqueux, la teneur en eau dudit solvant aqueux étant comprise entre 50 % et 100 %, de préférence entre 50 % et 75 %.
- Procédé selon la revendication 1, 2 ou 3, dans lequel ledit solvant aqueux est de l'éthanol aqueux contenant de l'ammoniac aqueux.
- Acide 7-[(7-(S)-amino-5-azaspiro[2.4]heptane-5-yl]-8-chloro-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydroquinoléine-3-carboxylique anhydre.
- Procédé selon l'une quelconque des revendications 1 à 4 pour l'obtention du 3/2 hydrate de l'acide 7-[(7-(S)-amino-5-azaspiro[2.4]heptane-5-yl]-8-chloro-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydroquinoléine-3-carboxylique sous forme cristalline, qui a essentiellement les caractéristiques de diffraction des rayons X suivantes:
Valeur de d (distance réticulaire) (Å) Intensité relative 11,47 faible 10,49 forte 9,69 faible 7,12 extrêmement faible 6,87 forte 6,23 forte 5,68 faible 5,25 forte 4,90 extrêmement forte 4,71 extrêmement faible 4,61 faible 4,25 faible 4,15 extrêmement faible 4,01 forte 3,85 extrêmement faible 3,80 extrêmement faible 3,74 extrêmement faible 3,69 faible 3,58 faible 3,50 faible 3,46 faible 3,39 faible 3,34 faible 3,29 faible 3,17 faible - Composition pharmaceutique contenant comme ingrédient actif une quantité thérapeutiquement efficace d'acide 7-[(7-(S)-amino-5-azaspiro[2.4]heptane-5-yl]-8-chloro-6-floro-1-[(1R,2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydroquinoléine-3-carboxylique anhydre.
- Utilisation de l'acide 7-[(7-(S)-amino-5-azaspiro[2.4]heptane-5-yl]-8-chloro-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydroquinoléine-3-carboxylique anhydre pour la préparation d'une composition pharmaceutique destinée au traitement d'infections bactériennes.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP22538093 | 1993-09-10 | ||
JP225380/93 | 1993-09-10 | ||
JP22538093 | 1993-09-10 |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0643058A1 EP0643058A1 (fr) | 1995-03-15 |
EP0643058B1 true EP0643058B1 (fr) | 1999-06-09 |
Family
ID=16828452
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP94114235A Expired - Lifetime EP0643058B1 (fr) | 1993-09-10 | 1994-09-09 | Cristaux d'un composé antimicrobien |
Country Status (32)
Country | Link |
---|---|
US (1) | US5693814A (fr) |
EP (1) | EP0643058B1 (fr) |
JP (1) | JP3793583B2 (fr) |
KR (1) | KR100336247B1 (fr) |
CN (1) | CN1057297C (fr) |
AT (1) | ATE181069T1 (fr) |
AU (1) | AU679094B2 (fr) |
BG (1) | BG61767B1 (fr) |
CA (1) | CA2131761C (fr) |
CZ (3) | CZ21598A3 (fr) |
DE (1) | DE69418953T2 (fr) |
DK (1) | DK0643058T3 (fr) |
ES (1) | ES2136142T3 (fr) |
FI (1) | FI110777B (fr) |
GE (1) | GEP19981355B (fr) |
GR (1) | GR3031012T3 (fr) |
HR (1) | HRP940506B1 (fr) |
HU (1) | HU224970B1 (fr) |
IL (2) | IL123910A (fr) |
LV (1) | LV11322B (fr) |
MY (1) | MY112574A (fr) |
NO (2) | NO307419B1 (fr) |
NZ (1) | NZ264422A (fr) |
PL (1) | PL180163B1 (fr) |
RU (1) | RU2126402C1 (fr) |
SG (1) | SG50492A1 (fr) |
SI (1) | SI9400349B (fr) |
SK (3) | SK283189B6 (fr) |
TW (1) | TW393481B (fr) |
UA (1) | UA41312C2 (fr) |
YU (1) | YU49132B (fr) |
ZA (1) | ZA946853B (fr) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE19546249A1 (de) * | 1995-12-12 | 1997-06-19 | Bayer Ag | Neue Kristallmodifikation des 1-Cyclopropyl-7-([S,S]-2,8-diazabicyclo[4,3,0]non-8-yl)-6-fluor-1,4-dihydro-8-methoxy-4-oxo-3-chinolincarbonsäure Hydrochlorid (CDCH), Verfahren zu dessen Herstellung und diese enthaltende pharmazeutische Zubereitungen |
JP3280388B2 (ja) * | 1997-06-26 | 2002-05-13 | ドング ホワ ファーマシューチカル インダストリアル カンパニー,リミテッド | キノロンカルボン酸誘導体 |
JP2001300293A (ja) * | 2000-04-25 | 2001-10-30 | Nipro Corp | 無機無水物または有機無水物の製造法 |
ITMI20032259A1 (it) | 2003-11-20 | 2005-05-21 | Chemi Spa | Nuovo polimorfo dell'acido 1-ciclopropil-7-(s,s-2,8-diazabciclo-4.3.0-non-8-il)-6-fluoro-1,4-diidro-8-metossi-4-oxo-chinolin carbossilico cloridrato e metodi per la sua preparazione |
CN102718746B (zh) * | 2012-06-18 | 2014-10-29 | 南京优科生物医药研究有限公司 | 西他沙星富马酸盐晶型a和其制药用途 |
CN103539776B (zh) * | 2012-07-16 | 2016-06-08 | 深圳信立泰药业股份有限公司 | 一种西他沙星晶型及其制备方法 |
CN106749174B (zh) * | 2016-12-06 | 2019-06-18 | 山东裕欣药业有限公司 | 一种西他沙星二水合物晶型、制备方法及其组合物片剂 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1065206A (zh) * | 1991-04-01 | 1992-10-14 | 战永胜 | 天然中草药防治早泄、淋病双效药液制法 |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE203719C (fr) * | 1907-11-02 | 1908-10-20 | ||
DK170473B1 (da) * | 1985-06-20 | 1995-09-11 | Daiichi Seiyaku Co | S(-)-pyridobenzoxazinforbindelser |
IL90062A (en) * | 1988-04-27 | 1994-10-07 | Daiichi Seiyaku Co | History of pyridonecarboxylic acid, their preparation and pharmaceutical preparations containing them |
CA1332605C (fr) * | 1988-10-03 | 1994-10-18 | Yasuhiro Nishitani | Acides pyridonecarboxyliques |
TW208013B (fr) * | 1990-03-01 | 1993-06-21 | Daiichi Co Ltd | |
US4994809A (en) * | 1990-03-07 | 1991-02-19 | Hughes Aircraft Company | Polystatic correlating radar |
MY109714A (en) * | 1990-10-18 | 1997-04-30 | Daiichi Seiyaku Co | Process for preparing 8-chloroquinolone derivatives |
WO1993025545A1 (fr) * | 1992-06-09 | 1993-12-23 | Korea Research Institute Of Chemical Technology | Nouveaux derives de quinoleine et procedes pour leur preparation |
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1994
- 1994-09-06 ZA ZA946853A patent/ZA946853B/xx unknown
- 1994-09-08 SK SK305-2002A patent/SK283189B6/sk unknown
- 1994-09-08 NZ NZ264422A patent/NZ264422A/en not_active IP Right Cessation
- 1994-09-08 CZ CZ98215A patent/CZ21598A3/cs not_active IP Right Cessation
- 1994-09-08 SK SK1076-94A patent/SK283188B6/sk unknown
- 1994-09-08 CZ CZ98214A patent/CZ21498A3/cs not_active IP Right Cessation
- 1994-09-08 SK SK306-2002A patent/SK283190B6/sk unknown
- 1994-09-08 NO NO943313A patent/NO307419B1/no unknown
- 1994-09-08 CZ CZ942176A patent/CZ284837B6/cs not_active IP Right Cessation
- 1994-09-08 UA UA94095787A patent/UA41312C2/uk unknown
- 1994-09-08 HR HR940506A patent/HRP940506B1/xx not_active IP Right Cessation
- 1994-09-09 BG BG99035A patent/BG61767B1/bg unknown
- 1994-09-09 AT AT94114235T patent/ATE181069T1/de not_active IP Right Cessation
- 1994-09-09 PL PL94304989A patent/PL180163B1/pl not_active IP Right Cessation
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Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN1065206A (zh) * | 1991-04-01 | 1992-10-14 | 战永胜 | 天然中草药防治早泄、淋病双效药液制法 |
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